Purposeful science – Lasting patient impact
We are building a pipeline of rationally designed gene therapy product candidates, pioneering a shift to treat not only rare but also prevalent diseases.
Our initial focus is on diseases of the heart and the nervous system, where we foresee a transformational change in the treatment paradigm similar to what has happened in the treatment of cancers. This is because advances in science are identifying new genes associated with diseases of the heart and the nervous system, making a compelling case for genetic medicines. The heart and nervous system represent organs where targeted delivery of the therapeutic genetic payload is currently inadequate. Our ART platform gives us an advantage to address these limitations and develop potentially first-in-class or best-in-class product candidates that may be safer and more effective.
Genetic medicines for the heart
We have applied ART to rationally design a new class of capsids with improved targeting of the heart muscle. In animal studies, our novel capsids administered as a simple intravenous (IV) infusion have been shown to reach almost all heart cells with homogeneous distribution. In contrast, conventional capsids such as AAV or rh74 reached less than 20% of cells at the same dose with a sporadic, patchy distribution pattern. The doses we studied are much lower than what is currently being tested in gene therapy trials for cardiac diseases. Reaching the predominant number of cardiomyocytes in a homogenous manner has been a long-standing limitation in the treatment of diseases of the heart such as genetic cardiomyopathies, life-threatening arrythmias, and heart failure. We believe we’ve solved this limitation.
AFTX-201, an investigational therapy for BAG3-associated dilated cardiomyopathy
Using our novel heart capsid, we’ve rationally designed an investigational gene therapy, AFTX-201, for BAG3-associated dilated cardiomyopathy (BAG3 DCM). AFTX-201 is intended to target the tissues most affected by the disease, allowing a much lower dose than otherwise would be required and potentially improving safety and effectiveness.
BAG3 DCM is a devastating monogenic heart disease affecting more than 70,000 people in the U.S., Europe, and U.K. regions alone. The BAG3 gene, or Bcl2-associated athanogene 3, encodes for a protein that is critical to the normal structure and function of muscle cells, particularly those in the heart. People affected by BAG3 DCM have a defect in the BAG3 gene resulting in an insufficient amount of functioning BAG3 protein thereby causing heart failure that begins typically in young adulthood and progresses rapidly. Whereas there are treatments for general heart failure, these do not address the underlying genetic cause of BAG3 DCM and unfortunately, almost 25% of patients require a heart transplant.
We designed AFTX-201, our investigational medicine for BAG3 DCM, to address the underlying root cause of the disease by delivering a fully functional copy of the BAG3 gene to the cells that need it most, heart cells. Because we use our novel heart capsid, we believe AFTX-201 can reach almost all heart cells much more than other investigational medicines using conventional capsids such as AAV or rh74 could. AFTX-201 is meant to be administered as a ‘one-and-done’ dose, via a simple IV infusion. In a genetic mouse model of BAG3 DCM, which mirrors the human disease, AFTX-201 showed the desired increase in BAG3 protein level in the heart, improvement in structural abnormalities of the heart, and complete restoration of cardiac function four weeks after a one-time IV dose. In contrast, the same gene construct delivered using a conventional capsid did not show adequate improvement in cardiac function in the same genetic mouse model. The dose we studied is much lower than what is currently being tested in other gene therapy clinical trials for cardiac diseases. We’re excited to advance this program towards an investigational new drug application and clinical trial initiation soon in the U.S. and elsewhere, in order to provide hope and potentially transformative benefit to people affected by BAG3 DCM.
We’ve presented our findings at multiple scientific conferences. To see this breakthrough science, please click here.
Research efforts in other heart diseases
We are testing a number of additional product candidates in preclinical studies to evaluate safety and effectiveness in other devastating diseases affecting the heart.
We’ve presented our findings at a scientific conference. To see this breakthrough science, please click here.
Genetic medicines for the nervous system
We have applied ART to rationally design a new class of capsids that target the nervous system by crossing the blood-brain-barrier (BBB), a protective system that generally prevents capsids from reaching the brain. In animal studies, our novel capsids given as simple intravenous infusion have been shown to cross the BBB and reach the majority of neurons, which are the main cell types of interest in many CNS diseases. In contrast, conventional capsids such as AAV reached less than 5% of neurons at the same dose. Crossing the BBB has been considered a key barrier to the treatment of diseases such as amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, and Huntington’s disease.
We are testing a number of product candidates in animal models to evaluate safety and efficacy in devastating diseases of the nervous system.
We’ve presented our findings at scientific conferences. To see our breakthrough science, please click here.
